The applicant previously focused his research on molecular aspects of steroid hormone biosynthesis. He recently assumed a position as Assistant Professor of Pediatrics in the UCLA School of Medicine. To further his career, as an independent investigator, he has established relationships with experts in the fields of ovarian physiology, insulin signaling, sensitivity and secretion. Under their mentored supervision, the candidate will initiate studies to address the childhood origins of the polycystic ovary syndrome (PCOS). PCOS is a heterogeneous clinical entity characterized by the post-pubertal onset of menstrual irregularities and excessive production of male hormones. PCOS is the most common endocrine disorder of women of reproductive age, affecting 5-10% of women worldwide. Insulin resistance is a necessary antecedent of both type 2 diabetes mellitus (T2DM) and the hormonal imbalances characteristic of PCOS. As insulin resistance is a transient physiologic phenomenon of normal pubertal maturation, the applicant hypothesizes that the requisite insulin resistance of PCOS must be expressed initially during pubertal progression. Cross- sectional and longitudinal studies will describe the patterns of insulin sensitivity that emerge throughout puberty in young women. Initially, the applicant will contrast the insulin sensitivity achieved on frequently sampled intravenous (iv) glucose tolerance tests between two matched sets of 25 subjects from families with, and without, histories of PCOS, at each of two distinct stages of puberty. He will then test the hypothesis that insulin resistance evolving throughout puberty in 40 girls at high risk for development of PCOS differs qualitatively and quantitatively in its pattern of expression, when compared with an equal number of adolescent controls. The applicant will measure specific biophysical and biochemical parameters to determine whether changes in these easily-obtained indices correlate with and predict changes in insulin sensitivity. To begin to elucidate the cellular mechanism for this unique form of insulin resistance, the applicant further proposes to obtain needle biopsies of insulin-responsive muscle from select subjects who demonstrate extremes of insulin sensitivity in the cross- sectional study. The applicant will assess the integrity and function of specific molecules necessary for cellular transmission of the insulin signal, to determine whether changes in these effectors might be responsible for evolving insulin resistance in at-risk individuals. This work will provide insight into the earliest relationship between PCOS and insulin resistance, at the whole-body and cellular level. Enhanced understanding of these fundamental events may permit earlier detection and intervention, thus preventing the profound physiological consequences of unabated T2DM associated with PCOS.